Chronic fetal exposure to polydrug use during pregnancy has reached epidemic proportions in some urban centers. One of the most common drug combinations is the maternal use of cocaine and alcohol, which has been linked to fetal growth retardation, neurobehavioral sequelae and congenital structural defects. At the cellular level, repeated intrauterine drug exposure has been shown to induce presynaptic and postsynaptic changes in the monoaminergic receptor pathways in the central nervous system. Much less is known regarding the effect of chronic prenatal drug exposure on peripheral autonomic function, specifically that of the cardiovascular system. However, mounting evidence of abnormal neonatal cardiac function associated with gestational exposure to cocaine, either alone or in combination with other illicit drugs, have been reported clinically. We will use a chronic rat model to test the hypotheses that maternal cocaine use alone or in combination with alcohol (1) changes the postsynaptic myocardial B adrenergic receptor signaling pathway and alters its modulation by cholinergic neurotransmitters and autonomic neuropeptides, neuropeptide Y and vasoactive intestinal peptide; (2) enhances the presynaptic sympathetic neural development and function and (3) modifies postnatal myocardial contractile function and autonomic responsiveness in the neonatal rat heart. Our specific aims will be (1) to examine the postsynaptic myocardial bataAR pathway and its modulation by the muscarinic, NPY and VIP receptor pathways; and to establish the changes due to chronic prenatal drug exposure; (2) to determine presynaptic adrenergic activity in the neonatal heart and document the effect of drug exposure on norepinephrine synthesis, availability, turnover and reuptake; (3) to elucidate the effect of drug exposure on cardiac rhythm and contractile function; and the myocardial contractile response to exogenously administered positive and negative inotropic agents. In addition, we will develop a chronic vasoconstrictor model in the pregnant rat to elucidate the primary fetal effects of cocaine from those secondary to its effects on the mother. Knowledge gained from the proposed research will provide a better understanding of the mechanism of drug injury and possible functional alterations in the heart resulting from prenatal exposure to cocaine and/or alcohol.